Article Text
PDF
Abstract
Aims To investigate the frequency of IgG4-related disease (IgG4-RD) among patients previously diagnosed with idiopathic sclerosing orbital inflammation (ISOI), and to compare the clinical features and treatment outcomes of patients with ISOI associated with IgG4-RD and those without IgG4.
Methods Retrospective clinicopathological series of 24 patients with ISOI diagnosed between June 2001 and June 2010. Biopsy specimens were immunostained for IgG-expressing and IgG4-expressing cells. Clinical data of patients with IgG4-RD and ISOI unrelated to IgG4 were obtained from patient records.
Results Of 24 patients, 11 patients (45.8%) were identified with IgG4-RD. 10 patients (10/11, 90.9%) presented with bilateral lacrimal gland enlargement, and seven of those also had submadibular gland enlargement. One patient (1/11, 9.1%) presented with a superior orbital mass. All patients were successfully treated with steroids and/or radiotherapy or had an indolent clinical course. 13 patients (54.2%) were identified with ISOI unrelated to IgG4. Eight patients (8/13, 61.5%) showed unilateral orbital involvement, and nine patients (9/13, 69.2%) had orbital lesions not involving the lacrimal glands. Treatment modalities for ISOI unrelated to IgG4 were varied and less effective: eight patients (61.5%) relapsed following initial treatment with steroids or radiation, and additional therapies were required to enter remission.
Conclusions IgG4-RD may be identified frequently in patients with ISOI, and distinguishing features may be bilateral lacrimal gland enlargement with associated submandibular gland enlargement. Patients with IgG4-RD may have better treatment outcomes with less aggressive treatment modalities than those with ISOI unrelated to IgG4. An additional workup for IgG4-RD should be considered in all histopathological biopsy specimens suspicious of ISOI.
- Lacrimal gland
- Orbit
- Pathology
- Inflammation
Statistics from Altmetric.com
Introduction
Idiopathic sclerosing orbital inflammation (ISOI) is a chronic inflammatory condition that is characterised by an insidious, aggressive, chronic and progressive sclerosing process. ISOI is a rare disease representing approximately 6.8% of all inflammatory orbital lesions1 and is recognised as a discrete entity of orbital inflammatory diseases different from the more common idiopathic orbital inflammation. An open biopsy is useful in the diagnosis of ISOI2 and the histopathological examination reveals a dense fibrosis with paucicellular infiltrate consisting of lymphocytes as well as few histiocytes, eosinophils and plasma cells.1 ,3 ,4
An IgG4-related disease (IgG4-RD) was recently defined as an inflammatory disorder characterised by IgG4-positive lymphoplasmacytic infiltrative lesions and elevated serum IgG4 level.5 ,6 It is considered to be an autoimmune disease involving multiple organs inclusive the ocular adnexa.7 ,8 Typical histopathological findings of an IgG4-RD include the infiltration of numerous IgG4-positive lymphoplasma cells, sclerosing fibrosis and reactive lymphoid follicles.5–8
An IgG4-RD is often likely to have systemic involvement,7 ,8 but ISOI also has been reported to be associated with other systemic sclerosing diseases such as retroperitoneal fibrosis, sclerosing cholangitis and Riedel's thyroiditis.4 ,9 Besides the clinical characteristics, histopathological similarities between ISOI and IgG4-RD have made it difficult to clarify these mass lesions. However, they should be differentiated from each other because the therapeutic strategies and prognosis may be different. Given the previous low awareness of IgG4-RD in the past, immunohistological workup for IgG and IgG4 was not carried out during the investigation for ISOI. Because none of the previous studies looked for this issue, it is difficult to conclude the role that IgG4 has in ISOI and the possibility that ISOI has been widespread diagnosed and overtreated.
The purpose of this study was to investigate the frequency of IgG4-RD among patients previously diagnosed with ISOI, and to compare the clinical features and treatment outcomes of patients with ISOI associated with IgG4-RD and those without IgG4.
Materials and methods
The study adhered to the tenets of the Declaration of Helsinki. Original pathological reports of all biopsied lesions in the department of ophthalmology at Samsung Medical Center, Seoul, Korea, during the period from June 2001 and June 2010 were reviewed from the database. The time period was chosen to be prior to the time when we began the routine immunohistological workup for orbital inflammatory disorders. A total of 65 cases with the pathological report of orbital inflammation or fibrosis were retrospectively identified, and their charts were reviewed to select the patients with ISOI. ISOI was originally diagnosed according to the clinical and radiological evidences of orbital inflammatory lesions without any known localised or systemic causes, and it was confirmed in all cases by biopsy-proven sclerosing inflammation characterised by the presence of marked fibrosis associated with mixed chronic inflammatory infiltrates of lymphocytes, plasma cells and histiocytes.
The inclusion criteria for the study consisted of the initial diagnosis of ISOI and the availability of pathological materials for the performance of additional immunohistopathological stains. The medical charts of the patients were reviewed, and the following data were collected: age at time of presentation, gender, lesion sites, laterality, clinical investigations, management, disease course and outcome.
Serial 4 µm-thick sections were sliced from formalin-fixed and paraffin-embedded tissue blocks. Immunohistochemical staining was performed using the antibodies against IgG (mouse monoclonal, A57H, dilution 1:400, code no. M828, DAKO, Copenhagen, Denmark) and IgG4 (mouse monoclonal, HP6025, dilution 1:2000, code no. MP011, The Binding Site, Birmingham, UK).
To confirm the diagnosis of IgG4-RD, the degree of IgG4-positive plasma cell infiltration was evaluated. The areas with the highest density of positive cells were evaluated to analyse the degree of IgG-positive or IgG4-positive plasma cells. Three high-power fields (HPFs) in each section were counted and an average number of positive cells per HPF (40×objective, 10×eyepiece) was calculated. The proportion of IgG4-positive/IgG-positive cells was considered significantly elevated when above 40%.
Results
Twenty-four consecutive cases of biopsy-proven ISOI (12 men, 12 women; age range 22–77 years; mean age 46.5 years) were identified. Locations of lesions were as follows: bilateral lacrimal gland, 13 (54.2%); superior extraconal, 6 (25%); inferior extraconal, 3 (12.5%); intraconal, 1 (4.2%) and unilateral lacrimal gland, 1 (4.2%).
Of 24 patients, 11 patients (45.8%) were identified with IgG4-RD. The clinical data for those 11 patients are presented in table 1 and figures 1 and 2. Five patients were men and six were women. The mean age at time of presentation was 50.2 years (range 36–64 years). The most common locations were the bilateral lacrimal glands (10/11) and the other was the superior extraconal orbit (1/11). Of 10 patients (10/11, 90.9%) with bilateral lacrimal gland enlargement, seven patients (7/10, 70%) also had submandibular salivary gland enlargement (figure 3). Besides lacrimal or submandibular glands, five patients (5/11, 45.5%) revealed other sites of involvement, including sinonasal cavity, nasopharynx, pancreas, skull base, pulmonary hilum, prostate gland and lymph nodes. In all cases revealed, the histological examinations marked lymphoplasmacytic infiltrations with stromal fibrosis, which were consistent with sclerosing inflammation. Immunostaining demonstrated high IgG4:IgG ratios ranging from 61% to 89% (table 1).
Clinicopathological and immunological findings, treatments and outcomes of IgG4-related disease
Clinical characteristics of each patient group with regard to locations of lesions (upper circle) and bilaterality (lower bar). ISOI, idiopathic sclerosing orbital inflammation.
Treatment modalities for each patient group (upper circle) and response to the treatment (lower bar). ISOI, idiopathic sclerosing orbital inflammation.
Case 10. A 49-year-old man was referred with 4-month history of bilateral upper lid swelling. Clinical examination and MRI images disclosed bilateral lacrimal (A, C, D) and submandibular (B) gland enlargement and soft-tissue mass involving paranasal sinuses. The fluorodeoxyglucose (FDG)-positron emission tomography (PET) revealed accumulations not only in above lesions but also in nasopharynx, hilar area, pancreatic head, prostate gland and multiple lymph nodes in parapharyngeal, cervical, supraclavicular, mediastinal, pulmonary hilar and gastric areas (E). An incisional biopsy of the lacrimal gland was performed and histopathological findings included a marked lymphoplasmacytic infiltration with stromal fibrosis consistent with a sclerosing inflammation (F, original magnification: 5×objective, 10×eyepiece). An additional immunostaining identified numerous IgG4-positive plasma cells (H, J), accounting for 68% of the IgG-positive plasma cells (G, I). The lacrimal and submandibular gland enlargement and the paranasal sinus mass responded well to oral prednisolone taper following intravenous corticosteroid. Five months after the steroid therapy, the patient showed a much decreased upper lid swelling (K).
Therapeutic modalities and outcomes were evaluated for the patients with IgG4-RD (table 1 and figure 2). All patients showed a good response to their treatment or had an indolent clinical course. There were four different treatment regimens: steroids alone (8/11); radiation alone (1/11); steroids and radiation (1/11) and no treatment (1/11). The mainstay of treatment was the administration of orally (5/8) or intravenously (3/8) applied systemic corticosteroids. However, one patient with liver cirrhosis (case 3) was treated with radiation due to the contraindication for systemic steroids. Another patient with superior orbital mass (case 4) relapsed on a reduced dose of steroids and achieved its remission after additional radiation. Another patient (case 1) refused treatment, but showed an indolent clinical course for 44 months.
Of 24 patients, 13 patients (54.2%) did not meet the immunohistochemical criterion for IgG4-RD and were identified with ISOI. The clinical data for those 13 patients with ISOI unrelated to IgG4 are presented in table 2 and figure 1. Seven patients were men and six were women. The mean age at time of presentation was 43.5 years (range 22–77 years). Orbital involvement of ISOI was bilateral in five of 13 patients (39%), and the locations of lesions were more various than those of IgG4-RD, including lacrimal gland (4/13), inferior orbit (3/13), superolateral orbit (3/13), superior orbit (2/13) and intraconal space (1/13). Four patients had extraocular muscle enlargement. Therapeutic modalities for ISOI to enter remission were also more diverse and aggressive than those for IgG4-RD (table 2 and figure 2). There were five different treatment regimens: steroids alone (4/13); steroids and radiation (4/13); steroids, radiation and additional chemotherapeutic agents, such as methotrexate, ciclosporin and cyclophosphamide (3/13); steroids and cyclophosphamide (1/13) and radiation alone (1/11).
Clinical characteristics, treatments and outcomes of idiopathic sclerosing orbital inflammation unrelated to IgG4
Discussion
ISOI is considered to be a distinct entity different from non-specific orbital inflammation and requires special attention and aggressive treatment.1–4 ISOI can be one potential presentation of systemic fibrosis disease, known as idiopathic multifocal fibrosclerosis, which includes idiopathic retroperitoneal fibrosis, sclerosing cholangitis, mediastinal fibrosis and Riedel's thyroiditis.1–4 ,10 ,11 IgG4-RD has similarities with ISOI in morphology and clinical features. The histopathological appearance of IgG4-RD simulates that of ISOI at areas with prominent fibrosis mingled with lymphocytes and plasma cells. It is also well known that IgG4-RD can involve multiple organs.
It is obvious that the emergence of IgG4-RD has reduced the group of patients with idiopathic inflammatory disorders or sclerosing conditions.12 Zen et al13 ,14 reviewed the histological appearance of inflammatory pseudotumours of the liver and lung and found that some populations of them were the hepatic and pulmonary counterparts of IgG4-RD. Nagai et al15 reported a case of suspected ISOI that showed an elevated serum IgG4 level and a good response to low-dose corticosteroid treatment.
Recently, clinical, histopathological and radiological features of IgG4-RD with orbital involvement have been described.16–18 Lacrimal glands were the most common orbital lesions, but extraglandular lesions such as medial canthus, extraconal space, extraocular muscles and lacrimal sacs were reported to be affected in IgG4-RD.16 ,17 In addition, enlargement of the infraorbital nerve and canal strongly suggests a diagnosis of reactive lymphoid hyperplasia or IgG4-RD in the presence of extraocular muscle enlargement or sinus disease.18 However, none of previous series1 ,10 about ISOI reviewed the role of IgG4. So, the present study aimed to identify unrecognised IgG4-RD in patients who were previously diagnosed with ISOI based on clinical and conventional histological examinations.
Given the previous low awareness of IgG4-RD, we carried out an additional immunohistological workup for IgG and IgG4 in 24 patients who were diagnosed with ISOI by histopathological examination performed between 2001 and 2010. It is interesting that 11 (45.8%) of 24 cases initially diagnosed with ISOI were, in fact, identified to be IgG4-RD. This result emphasises our initial suspicion that IgG4-RD has been under-recognised until now, and it may be culled from the ISOI pool. Of the 11 cases with an IgG4-RD, 10 (90.9%) presented with bilateral lacrimal gland enlargement and seven of those (70%) also had submandibular gland enlargement. It corresponds to recent evidences suggesting that chronic sclerosing dacryoadenitis is likely to be an IgG4-RD.6 ,19 ,20 In contrast, the patients with ISOI unrelated to IgG4 showed different clinical features. They had unilateral orbital involvement in eight of 13 patients (61%), and dacryoadenitis was present in only four, and the others (9/13, 69%) had extraconal and/or intraconal orbital lesions not involving the lacrimal glands. The awareness for the typical clinical presentation of an ocular adnexal IgG4-RD is important to convince physicians of additional immunohistological stains and serum IgG4 workup.
Although the conventional histological findings are similar in ISOI and IgG4-RD, they should be differentiated from each other because the therapeutic strategies and prognosis are different. Unfortunately, the infrequency of these diseases has made it difficult to perform prospective trials and establish an optimal treatment. Nonetheless, IgG4-RD is likely to benefit from corticosteroids, whereas ISOI may require more aggressive treatments.10 ,12
For the treatment of ISOI in the present study, the authors mostly conducted a trial of high-dose corticosteroids first, with a low threshold to add radiation and/or chemotherapy if there is no dramatic improvement. The majority of patients with IgG4-related dacryoadenitis (10/11) revealed a good response to the conventional treatment including systemic corticosteroids alone (8/10) or radiation alone (1/10), except one patient (1/10) having an indolent clinical course for 44 months even without any treatment. However, one patient with a superior orbital mass showed an unsustainable response to corticosteroid and required additional radiation as well as maintenance corticosteroid at a dose of 10 mg/day to enter remission.
With regard to the treatment for ISOI unrelated to IgG4 in the present study, eight patients (8/13, 62%) had some relapse following initial treatment with systemic corticosteroids or radiation. Additional therapies were required to enter remission for these patients, including supplemental radiotherapy with corticosteroids, and chemotherapeutic agents, such as cyclophosphamide, methotrexate or ciclosporin. Interestingly, four patients with dacryoadenitis unrelated to IgG4 received systemic corticosteroids (3/4) or radiation (1/4), and all of them had a good response without any additional treatment. Of the nine patients with ISOI except dacryoadenitis, however, eight required combination therapies and only one had a good response to corticosteroids alone.
The doctors should consider searching for evidences of IgG4-RD in the setting of ISOI, especially in patients with lacrimal gland enlargement. It is because those patients have high frequency of IgG4-RD, and those may have a good profile in terms of response to treatment and prognosis even in cases unrelated to IgG4.
This study has important limitations mostly stemming from its retrospective design. The serum IgG4 levels were not checkable and a careful systemic workup was not performed in most cases due to the low awareness of IgG4-RD and its systemic involvement in the past. An elevated serum IgG4 (≥135 mg/dL) is one of the diagnostic criteria, but is considered to be a less reliable marker than immunostaining for tissue IgG4-positive cells.7 ,8 ,12 Associations with allergic rhinitis, elevated serum IgE, lymphadenopathy and extranodal mucosa-associated lymphoid tissue (MALT) lymphoma12 ,21 also would have been worth to be investigated in the comparison of IgG4-RD and ISOI groups. Especially, lymphoma can arise from IgG4-related dacryoadenitis,22 and about 10% (44/448) of patients with MALT lymphoma were reported to be IgG4-related cases in Japan.23 Whereas, we could not investigate those relationships, as we did not include the patients with MALT lymphoma, but those with ISOI for this study. Although there was no IgG4-related case complicating lymphoma during follow-up in this study, prospective studies are required to ascertain whether the pathological change of lymphoproliferative infiltration in IgG4-RD can develop even after the treatment with corticosteroids or radiation.
Although it is still unclear whether the IgG4-RD is a specific entity or just an immune-mediated epiphenomenon of a sclerosing orbital inflammation, our results bring attention to the frequent IgG4-related conditions in the group of patients with ISOI. The key clinical features raising a strong suspicion for an IgG4-RD are bilateral lacrimal gland enlargement with associated submandibular gland enlargement. Patients with IgG4-RD may have better treatment outcomes with less aggressive treatment modalities than those with ISOI unrelated to IgG4. We suggest an additional workup for IgG4-RD in all histopathological biopsy specimens suspicious of ISOI to avoid overly aggressive treatment.
References
Footnotes
Contributors All authors substantially contributed to conception and design of the study, data acquisition, analysis and interpretation of data, drafting and revising the manuscript (according to International Committee of Medical Journal Editors (ICMJE) requirements).
Competing interests None declared.
Patient consent Obtained.
Ethics approval The ethics committee approval was obtained from the institutional review board ofSamsung Medical Center, Seoul, Korea.
Provenance and peer review Not commissioned; externally peer reviewed.
Linked Articles
- At a glance